The autophagy machinery has been shown to mediate host responses against a variety of infectious agents. These responses include the lysosomal degradation of specific pathogens via canonical autophagy, as well interferon-y-dependent killing of other pathogens via non-degradative pathways. Developing small molecules that enhance autophagy (ATG) protein-dependent pathways may have the potential to yield therapeutics against a broad spectrum of organisms. The proposed project applies next-generation synthetic chemistry and high-throughput screening to discover novel enhancers of ATG-mediated defense to pathogen infection. The project includes both phenotypic and target-based screens to discover modulators of autophagy and ATG-dependent processes, which will be tested for their activity against a range of pathogens of interest to the NIAID. Compounds with broad activity will be characterized for their mechanisms-of-action and developed further through medicinal chemistry to yield therapeutic leads suitable for testing treatment strategies in animal studies.